Self administered cognitive screening test (TYM) for detection of Alzheimer’s disease: cross sectional study

Objective To evaluate a cognitive test, the TYM (“test your memory”), in the detection of Alzheimer’s disease

Spectrum, risk factors and outcomes of neurological and psychiatric complications of COVID-19: a UK-wide cross-sectional surveillance study.

SARS-CoV-2 is associated with new-onset neurological and psychiatric conditions. Detailed clinical data, including factors associated with recovery, are lacking, hampering prediction modelling and targeted therapeutic interventions. In a UK-wide cross-sectional surveillance study of adult hospitalized patients during the first COVID-19 wave, with multi-professional input from general and sub-specialty neurologists, psychiatrists, stroke physicians, and intensivists, we captured detailed data on demographics, risk factors, pre-COVID-19 Rockwood frailty score, comorbidities, neurological presentation and outcome. A priori clinical case definitions were used, with cross-specialty independent adjudication for discrepant cases. Multivariable logistic regression was performed using demographic and clinical variables, to determine the factors associated with outcome. A total of 267 cases were included. Cerebrovascular events were most frequently reported (131, 49%), followed by other central disorders (95, 36%) including delirium (28, 11%), central inflammatory (25, 9%), psychiatric (25, 9%), and other encephalopathies (17, 7%), including a severe encephalopathy (n = 13) not meeting delirium criteria; and peripheral nerve disorders (41, 15%). Those with the severe encephalopathy, in comparison to delirium, were younger, had higher rates of admission to intensive care and a longer duration of ventilation. Compared to normative data during the equivalent time period prior to the pandemic, cases of stroke in association with COVID-19 were younger and had a greater number of conventional, modifiable cerebrovascular risk factors. Twenty-seven per cent of strokes occurred in patients 60 years old, the younger stroke patients presented with delayed onset from respiratory symptoms, higher rates of multi-vessel occlusion (31%) and systemic thrombotic events. Clinical outcomes varied between disease groups, with cerebrovascular disease conferring the worst prognosis, but this effect was less marked than the pre-morbid factors of older age and a higher pre-COVID-19 frailty score, and a high admission white cell count, which were independently associated with a poor outcome. In summary, this study describes the spectrum of neurological and psychiatric conditions associated with COVID-19. In addition, we identify a severe COVID-19 encephalopathy atypical for delirium, and a phenotype of COVID-19 associated stroke in younger adults with a tendency for multiple infarcts and systemic thromboses. These clinical data will be useful to inform mechanistic studies and stratification of patients in clinical trials

Social cognitive deficits and their neural correlates in progressive supranuclear palsy

Although progressive supranuclear palsy is defined by its akinetic rigidity, vertical supranuclear gaze palsy and falls, cognitive impairments are an important determinant of patients’ and carers’ quality of life. Here, we investigate whether there is a broad deficit of modality-independent social cognition in progressive supranuclear palsy and explore the neural correlates for these. We recruited 23 patients with progressive supranuclear palsy (using clinical diagnostic criteria, nine with subsequent pathological confirmation) and 22 age- and education-matched controls. Participants performed an auditory (voice) emotion recognition test, and a visual and auditory theory of mind test. Twenty-two patients and 20 controls underwent structural magnetic resonance imaging to analyse neural correlates of social cognition deficits using voxel-based morphometry. Patients were impaired on the voice emotion recognition and theory of mind tests but not auditory and visual control conditions. Grey matter atrophy in patients correlated with both voice emotion recognition and theory of mind deficits in the right inferior frontal gyrus, a region associated with prosodic auditory emotion recognition. Theory of mind deficits also correlated with atrophy of the anterior rostral medial frontal cortex, a region associated with theory of mind in health. We conclude that patients with progressive supranuclear palsy have a multimodal deficit in social cognition. This deficit is due, in part, to progressive atrophy in a network of frontal cortical regions linked to the integration of socially relevant stimuli and interpretation of their social meaning. This impairment of social cognition is important to consider for those managing and caring for patients with progressive supranuclear palsy

Focal posterior cingulate atrophy in incipient Alzheimer's disease

Severe posterior cingulate cortex hypometabolism is a feature of incipient, sporadic Alzheimer's disease (AD). The aim was to test the hypothesis that this region is focally atrophic in very early disease by studying AD patients at the mild cognitive impairment (MCI) stage, and, if so, to determine whether the amount of atrophy was comparable to that of the hippocampus. Twenty-four patients meeting criteria for amnestic MCI, who all subsequently progressed to fulfil AD criteria, and 28 age-matched controls, were imaged with volumetric MRI. Four regions of interest were manually traced in each hemisphere: two posterior cingulate regions (BA 23 and BA 29/30), the hippocampus (as a positive control) and the anterior cingulate (as a negative control). BA 23 and BA 29/30 were both significantly atrophic and this atrophy was comparable to that found in the hippocampus, in the absence of anterior cingulate cortex (ACC) atrophy. Contrary to previous reports, there was no evidence that posterior cingulate atrophy is specifically associated with early-onset AD. The results indicate that posterior cingulate cortex atrophy is present from the earliest clinical stage of sporadic AD and that this region is as vulnerable to neurodegeneration as the hippocampus

Absolute diffusivities define the landscape of white matter degeneration in Alzheimer's disease

Recent imaging evidence in Alzheimer's disease suggests that neural involvement in early-stage disease is more complex than is encapsulated in the commonly held position of predominant mesial temporal lobe degeneration-there is also early posterior cingulate cortex and diencephalic damage. These findings suggest that early clinical Alzheimer's disease is underpinned by damage to an inter-connected network. If correct, this hypothesis would predict degeneration of the white matter pathways that connect this network. This prediction can be tested in vivo by diffusion magnetic resonance imaging. Most diffusion tensor imaging studies of white matter in neurodegenerative disorders such as Alzheimer's disease have concentrated on fractional anisotropy reductions and increased 'apparent' diffusivity; however, there is a lack of empirical biological evidence to assume that fractional anisotropy changes will necessarily capture the full extent of white matter changes in Alzheimer's disease. In this study, therefore, we undertook a comprehensive investigation of diffusion behaviour in Alzheimer's disease by analysing each of the component eigenvalues of the diffusion tensor in isolation to test the hypothesis that early Alzheimer's disease is associated with degeneration of a specific neural network. Using tract-based spatial statistics, we performed voxel-wise analyses of fractional anisotropy, axial, radial and mean diffusivities in 25 Alzheimer's disease patients compared with 13 elderly controls. We found that increased absolute (axial, radial and mean) diffusivities in Alzheimer's disease were concordant in a distribution consistent with the network hypothesis, highly statistically significant and far more sensitive than fractional anisotropy reductions. The former three measures identified confluent white matter abnormalities in parahippocampal gyrus and posterior cingulum, extending laterally into adjacent temporo-parietal regions as well as splenium and fornix. The caudal occipital lobe, temporal pole, genu and prefrontal white matter were relatively preserved. This distribution is highly consistent with expected predictions of tract degeneration from grey matter lesions identified by fluorodeoxyglucose positron emission tomography and structural magnetic resonance imaging. Concordant with results from these other imaging modalities, this pattern predominantly involves degeneration of the tracts connecting the circuit of Papez. These findings also highlight that early neuropathological processes are associated with changes of the diffusion ellipsoid that are predominantly proportional along all semi-principal axes

Comparative reliability of total intracranial volume estimation methods and the influence of atrophy in a longitudinal semantic dementia cohort

BACKGROUND AND PURPOSE: Total intracranial volume (TIV) as a measure of premorbid brain size is often used to correct volumes of interest for interindividual differences in magnetic resonance imaging (MRI) studies. We directly compared the reliability of different TIV estimation methods to address whether such methods are influenced by brain atrophy in the neurodegenerative disease, semantic dementia. METHODS: We contrasted several manual approaches using T1-weighted, T2-weighted, and proton density (PD) acquisitions with 2 automated methods (statistical parametric mapping 5 [SPM5] and FreeSurfer [FS]) in a cohort of semantic dementia subjects (n = 11) that had been imaged longitudinally. RESULTS: Novel mid-cranial sampling of either PD or T2-weighted images were least susceptible to atrophy: of these, the PD method was both more precise and more user-friendly. SPM5 also produced good results, providing automation for only a small loss in precision compared to the best manual methods. The T1 method that underestimated TIV as atrophy progressed was the least reproducible and the most labor-intensive. Fully automated FS overestimated TIV with progressive atrophy, and the results were even worse after optimizing the transformation. CONCLUSION: The mid-cranial sampling of PD images achieved the best combination of precision, reliability, and user-friendliness. SPM5 is an attractive alternative if the highest level of precision is not required

Diffusion Tensor Metrics as Biomarkers in Alzheimer's Disease

<div><h3>Background</h3><p>Although diffusion tensor imaging has been a major research focus for Alzheimer’s disease in recent years, it remains unclear whether it has sufficient stability to have biomarker potential. To date, frequently inconsistent results have been reported, though lack of standardisation in acquisition and analysis make such discrepancies difficult to interpret. There is also, at present, little knowledge of how the biometric properties of diffusion tensor imaging might evolve in the course of Alzheimer’s disease.</p> <h3>Methods</h3><p>The biomarker question was addressed in this study by adopting a standardised protocol both for the whole brain (tract-based spatial statistics), and for a region of interest: the midline corpus callosum. In order to study the evolution of tensor changes, cross-sectional data from very mild (N = 21) and mild (N = 22) Alzheimer’s disease patients were examined as well as a longitudinal cohort (N = 16) that had been rescanned at 12 months.</p> <h3>Findings and Significance</h3><p>The results revealed that increased axial and mean diffusivity are the first abnormalities to occur and that the first region to develop such significant differences was mesial parietal/splenial white matter; these metrics, however, remained relatively static with advancing disease indicating they are suitable as ‘state-specific’ markers. In contrast, increased radial diffusivity, and therefore decreased fractional anisotropy–though less detectable early–became increasingly abnormal with disease progression, and, in the splenium of the corpus callosum, correlated significantly with dementia severity; these metrics therefore appear ‘stage-specific’ and would be ideal for monitoring disease progression. In addition, the cross-sectional and longitudinal analyses showed that the progressive abnormalities in radial diffusivity and fractional anisotropy always occurred in areas that had first shown an increase in axial and mean diffusivity. Given that the former two metrics correlate with dementia severity, but the latter two did not, it would appear that increased axial diffusivity represents an upstream event that precedes neuronal loss.</p> </div

Longitudinal tensor behaviour in the splenium.

<p>Longitudinal pairs of mean subject skeletonised DTI parameters as a function of cognitive status (ACE-R) for Alzheimer’s disease subjects at baseline (blue) and 12 months (red).</p

Cross-sectional study of mild Alzheimer’s disease.

<p>TBSS results for the mild-stage Alzheimer’s disease group compared to controls. Thresholded (TFCE-P<0.05) statistical maps for increased axial/radial diffusivity and reduced FA were overlaid onto the mean FA skeleton and the MNI152 template. Coronal depths are given in millimetres.</p